The present invention concerns a process for producing L-carnitine by classical chemical optical resolution of D,L-carnitine nitrile salts using optically active N-acetylproline as the resolving agent and saponifying the resulting L-carnitine nitrile salt.
L-Carnitine is also known as vitamin B.sub.T and is being used increasingly in dietetic and pharmaceutical preparations for treatment of myocardial damage, chronic circulation disorders and to increase energy levels. Most chemical methods of synthesizing L-carnitine include chemical optical resolution of a racemic carnitine precursor. Resolution of the precursor D,L-carnitinamide chloride using an optically active acid (East German Patent 23,217, German Patents (OLS) 2,927,672 and 3,342,713) is known. A disadvantage of this process is especially the fact that D,L-carnitinamide chloride must first be synthesized from D,L-carnitine nitrile chloride. In comparison with resolution at the level of D,L-carnitine nitrile chloride, which can be saponified directly to carnitine, an additional step is thus necessary.
Resolution at the level of the carnitine precursor D,L-3-chloro-2-hydroxypropyltrimethylammonium chloride is known but is not completely satisfactory on an industrial scale (see European Patents A 157,315 and A 312,726).
Common features of resolution of D,L-carnitine nitrile salts such as D,L-carnitine nitrile chloride (which is synthesized in general by cyanidation of D,L-3-chloro-2-hydroxypropyltrimethylammonium chloride or D,L-epoxypropyltrimethylammonium chloride) include the conversion of the chloride to the hydroxide, reaction with an optically active acid, separation of the diastereomer salts and cleavage thereof with a strong acid, where the optically active carnitine nitrile salt is obtained and the starting optically active acid is recovered.
For example, D-tartaric acid and D-camphor-10-sulfonic acid have been proposed as optically active acids for resolution of carnitine nitrile chloride, but they necessitate frequent recrystallization of the diastereomer salts because of the low differences in solubility. An improvement was achieved by a combined use of D-camphor-10-sulfonic acid and dibenzoyl L-tartaric acid (E. Strack et al., Z. physiol. Chem. 318, 129 (1960)), but two resolving agents make the process expensive and unsuitable for industrial use. When only dibenzoyl L-tartaric acid is used, the difference in solubility between the two diastereomers is low and this in turn has a negative effect on yield.
Use of optically active N-acetylglutamic acid as the acidic resolving agent is also known for resolution of D,L-carnitine nitrile salts (Japanese Patent 43-8248, Dutch Patent A 6,614,321). In this optical resolution, it is not the naturally occurring N-acetyl-L-glutamic acid that is necessary but instead its antipode N-acetyl-D-glutamic acid which is not itself available in adequate amounts or must be synthesized by means of D-carnitine nitrile chloride. However, when N-acetyl-L-glutamic acid is used as the resolving agent and the insoluble salt of D-carnitine nitrile and N-acetyl-L-glutamic acid is first separated from the diastereomer mixture, production of an optically pure L-carnitine-N-acetyl-D-glutamate from the mother liquor requires multiple fractional crystallization which entails a considerable loss of yield.
In order to improve the efficiency of the aforementioned resolution and increase the optical purity of the desired L-carnitine nitrile salt, Japanese Patent A 62-286959 (1987) proposes first subjecting the mixture of diastereomer salts to fractional crystallization, then exchanging the optically active anion of the crude diastereomer containing mainly L-carnitine nitrile with an optically inactive acid anion (especially perchlorate or oxalate), and then purifying the resulting salt by means of further fractional crystallization. However, the cost of the process is greatly increased by this second fractional crystallization step. Furthermore, the yield is reduced especially by resolution on a production scale and this leads to higher costs for use and recovery of the optically inactive acid to be selected.
Japanese Patent 62-286959 mentions optically active N-acetylproline in addition to numerous other cleavage reagents but does not mention whether this acid should be used in the L or D form. In view of the practical example using N-acetyl-L-glutamic acid, where L-carnitine nitrile N-acetyl-L-glutamate is more difficult to crystallize than the (DL) salt and thus necessitates the second fractional crystallization step, those skilled in the art could have expected comparable results when using N-acetyl-L-proline that is readily accessible from naturally occurring raw materials, namely L-proline.
In the process according to German Patent Application P 40 15 573.0, optically active N-acetyl-2,2,5,5-tetraalkylthiazolidine-4-carboxylic acids are used as resolving agents for resolution of D,L-carnitine nitrile chloride. However, these resolving agents are accessible only by synthesis and they also require classical chemical optical resolution.